When The Brain Forgets Connections: The Discovery of the Brain Region That Causes Forgetting Loved Ones in Alzheimer's Disease
- Dec 3, 2025
- 4 min read
This study shows that social memory loss in Alzheimer's disease is linked to the destruction of perineuronal networks in the CA2 region of the hippocampus. When these networks disappear, synapses become vulnerable and memory deteriorates. Blocking the enzymes that destroy these structures may protect the brain and slow the progression of symptoms, indicating a new treatment possibility.
Alzheimer's disease is currently the leading cause of dementia worldwide, affecting tens of millions of people. It begins subtly, with minor memory lapses, difficulty maintaining attention, and behavioral changes. Over time, these symptoms intensify and begin to compromise a person's identity: names are forgotten, faces are no longer recognized, and social relationships become difficult.
These changes do not happen randomly, but are accompanied by profound transformations in the brain, such as the accumulation of toxic proteins called beta-amyloid and tau, the death of neurons, reduction of synaptic connections, and increased inflammation and oxidative stress.
In recent years, researchers have begun to observe another important alteration in the brain with Alzheimer's: changes in the extracellular matrix, which is the material that surrounds and supports neurons. Within this structure, there is a more organized form called the perineuronal network. These networks function as both protection and regulator of neuronal activity.
They are composed of molecules such as hyaluronic acid, specific proteins, and proteoglycans, including aggrecan. In regions essential for memory, such as the hippocampus, these networks surround cells that help control electrical activity and maintain the stability of synapses. A specific part of the hippocampus, called the CA2 region, is especially interesting because it participates in a type of highly social memory: the ability to recognize familiar individuals.
Several studies have shown that in the brain affected by Alzheimer's disease, these perineuronal networks are weakened or fragmented. This destruction is associated with inflammatory processes that increase enzymes capable of degrading the extracellular matrix. These enzymes include metalloproteinases, which function as "biological scissors," cutting cellular structures.
The hypothesis raised by the scientists is that when these networks break down, synapses become more vulnerable, leaving the brain less able to retain memories and more exposed to damage.
To test this hypothesis, the researchers used an animal model of Alzheimer's called 5XFAD, a type of mouse genetically modified to develop alterations similar to those seen in humans with the disease. The methodological aspect of this study is especially important because it shows how different scientific techniques can be combined to answer a single question.
First, the scientists used microscopy and biological markers to visualize the perineuronal networks in the brains of these animals. In parallel, they conducted behavioral tests to measure the mice's ability to recognize others of the same species. These tests are crucial because they translate microscopic changes into observable behaviors.
RNA sequencing methods were also used to identify which genes were being activated or deactivated in the CA2 region, allowing researchers to understand which biological mechanisms were at work. In addition, genetic manipulation and enzymatic digestion techniques were used to artificially remove perineuronal networks, testing whether their absence could, by itself, cause social memory loss.
Finally, drugs known to block metalloproteinase activity were administered to observe whether it would be possible to prevent damage and preserve cognitive function.
The results were clear: mice with Alzheimer's disease showed a marked reduction in perineuronal networks in the CA2 region, and this loss coincided with the appearance of social memory deficits. When researchers artificially disrupted these networks in healthy animals, these mice began to exhibit memory problems similar to those in the Alzheimer's model, demonstrating a cause-and-effect relationship.
Molecular analysis revealed that the enzymes responsible for cutting the extracellular matrix were abnormally increased, suggesting an imbalance between network destruction and repair.
The most promising step came when researchers treated the animals with a substance capable of inhibiting these enzymes. The treated mice preserved their perineuronal networks better and retained their social memory for longer.
These findings reveal not only that the loss of social memory in Alzheimer's is directly related to the destruction of these protective networks around CA2 neurons, but also show that this process can be slowed down. This opens the way for a new line of therapy that does not directly target the classic toxic proteins of Alzheimer's, but rather the environment that sustains neuronal connections.
READ MORE:
Degradation of perineuronal nets in hippocampal CA2 explains the loss of social cognition memory in Alzheimer's disease
Lata Chaunsali, Jiangtao Li, Erik Fleischel, Courtney E. Prim, Izabela Kasprzak, Shan Jiang, Silky Hou, Miguel Escalante, Elise C. Cope, Michelle L. Olsen, Bhanu P. Tewari, Harald Sontheimer
Alzheimer’s and Dementia. Volume21, Issue10, October 2025, e70813
Abstract:
Loss of social cognition memory impairs Alzheimer's disease (AD) patients to recognize family members, friends, and caregivers. We investigate the role of perineuronal nets (PNNs), specialized coats of extracellular matrix around hippocampal CA2 neurons in AD-associated social memory impairments. We utilized 5XFAD mouse model of AD and employed immunohistochemistry, microscopy, bulk RNA-sequencing, animal behavior, gene-knockout, and drug-treatment approaches. AD mice showed profound disruption of CA2 PNNs with concomitant impairment of social cognition memory. Genetic or enzymatic CA2 PNN disruption in wild-type mice mimicked these impairments. Transcriptomic analysis shows upregulation of PNN-cleaving matrix metalloproteinases (MMP) in AD mice causing disequilibrium of PNN synthesis and remodeling. Chronic inhibition of MMPs retains CA2 PNN and delays social memory impairments in 5XFAD mice. AD-associated social memory impairments are caused by loss of CA2 PNNs. Inhibition of PNN proteolysis by MMPs preserves social memory, suggesting PNN as a promising therapeutic target.
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